Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients

NCT03568383 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: A5300B/I2003B/PHOENIx12041
• Study Type: interventional
• Target: 5,832
• Locations: 13 countries
• Sites: 31

Brief Summary

The purpose of this study is to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active tuberculosis (TB) during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR-TB) (index cases). High-risk HHCs are those with HIV or non-HIV immunosuppression, latent TB infection, and young children below the age of 5 years.

Conditions

Tuberculosis, MDR

Keywords

Tuberculosis; Multidrug Resistance; Prevention; Household Contact

Outcome Measures

Primary Outcomes (2)

• Percent of participants with confirmed or probable active TB at any time between Day 0 and the week 96 study visit

  TB diagnoses will be reviewed by the independent outcomes review committee to assess whether the HHC had TB, if it was confirmed or probable TB, and if it was MDR-TB.

  Measured through Week 96

• Percent of participants who permanently discontinue randomized study drug (DLM or INH) due to a treatment-related adverse event

  Requiring discontinuation as defined in the protocol, or in the opinion of the site investigator is a treatment-limiting adverse event.

  Measured through Week 96

Secondary Outcomes (4)

• Percent of participants with confirmed active MDR-TB at any time between Day 0 and the week 96 study visit

  Measured through Week 96

• Percent of participants who died from any cause at any time between Day 0 and 96 weeks of follow-up

  Measured through Week 96

• Percent of participants who died from any cause at any time between Day 0 and 96 weeks of follow-up, or with confirmed or probable active TB at any time between Day 0 and the week 96 study visit

  Measured through Week 96

• Percent of participants with a Grade 3 or higher adverse event during the period receiving randomized study drug (DLM or INH)

  Measured through Week 26

Study Arms (2)

Arm A: Delamanid (DLM)

EXPERIMENTAL

HHCs will receive delamanid (DLM) for 26 weeks.

Drug: Delamanid (DLM)

Arm B: Isoniazid (INH)

EXPERIMENTAL

HHCs will receive isoniazid (INH) and pyridoxine (vitamin B6) for 26 weeks.

Drug: Isoniazid (INH); Dietary Supplement: Pyridoxine (vitamin B6)

Interventions

Delamanid (DLM) DRUG

Adults and children ≥30 kg: delamanid 200 mg orally once daily. Children ≥2.5 kg to \<30 kg: weight-band dosing orally once daily as per the study protocol. As children gain weight, their DLM dose should be adjusted, typically every month or as the visit schedule permits.

Arm A: Delamanid (DLM)

Isoniazid (INH) DRUG

Adults and children ≥24 kg: INH 300 mg orally once daily. Children ≥2.5 kg to \<24 kg: INH weight-band dosing orally once daily as per the study protocol. As children gain weight, their INH dose should be adjusted.

Arm B: Isoniazid (INH)

Pyridoxine (vitamin B6) DIETARY_SUPPLEMENT

All HHCs in Arm B must receive pyridoxine (vitamin B6) with each dose of INH based on the current local dosing guidelines. For children up to 3 years of age and nursing women, pyridoxine will be given as per local standard of care. Pyridoxine is not supplied through the study.

Arm B: Isoniazid (INH)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• INDEX CASE
• Men and women age greater than or equal to 18 years.
• Pulmonary MDR-TB defined as:
• Confirmation of rifampin/rifampicin (RIF) resistance and INH resistance by
• adequate source documentation (including date of testing, test methodology, and test results) of RIF and INH resistance from a licensed/nationally approved\* referral program, OR
• if either or both results are unknown or not adequately documented (as noted above), then confirmation must be obtained using a DAIDS-approved laboratory that operates according to Good Clinical Laboratory Practices (GCLP) guidelines and participates in an appropriate external quality assurance (EQA) program.
• \*NOTE: The term "licensed/nationally approved" refers to a laboratory that has been certified or licensed by an oversight body within that country and approved for RIF and/or INH resistance testing.
• Started MDR-TB treatment within the past 90 days.
• Ability and willingness of the index case to provide informed consent to access the HH and approach HH members for evaluation.
• HH of index case has at least one reported HHC.
• HOUSEHOLD CONTACTS
• If any member(s) of the HH is/are not eligible or do not want to participate, all other eligible TB contacts within the HH can still participate.
• Currently lives or lived in the same dwelling unit or plot of land and shares or has shared the same housekeeping arrangements as the index case and who reports exposure within 90 days prior to the index case starting MDR-TB treatment. Also, shared greater than 4 hours of indoor airspace with the index case during any one-week period prior to the index case starting MDR-TB treatment.
• HHCs must be in one of the following high-risk groups:
• All children 0 to less than 5 years old at the time of enrollment, regardless of LTBI or HIV status;

You may not qualify if:

• INDEX CASE
• Has previously enrolled into the A5300B/I2003B/PHOENIx trial as an index case or HHC, or is a member of a HH which has previously enrolled into the A5300B/I2003B/PHOENIx trial.
• HOUSEHOLD CONTACTS
• Current confirmed or probable or possible pulmonary or extrapulmonary TB, based on the following criteria: the current ACTG Diagnosis Appendix 100 for adults and for children of greater than or equal to 15 years of age; or the modified pediatric TB definitions for children less than 15 years of age as described in the A5300B/I2003B/PHOENIx MOPS.
• Receipt of more than 30 cumulative days of INH, rifamycin, fluoroquinolone, or DLM in the 90 days prior to study entry.
• History of or current liver cirrhosis at any time prior to study entry.
• Evidence of acute hepatitis, such as abdominal pain, nausea and vomiting, jaundice, dark urine, and/or light stools within 90 days prior to study entry.
• Peripheral neuropathy greater than or equal to Grade 2 within 90 days prior to study entry according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017.
• Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
• Current cardiovascular disorder that is clinically relevant in the opinion of the site investigator, including but not limited to heart failure, coronary heart disease, second or third degree atrioventricular (AV) block, prolongation of the QRS complex over 120 ms (in both male and female participants), arrhythmia, or tachyarrhythmia.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Serious illness requiring systemic treatment including parenteral therapy (e.g., antibiotics) and/or hospitalization within 30 days prior to study entry.
• Currently receiving other medication with potential for adverse drug-drug interactions, including QT prolongation. Please see the study protocol for a list of prohibited medications.
• Taken an investigational drug or vaccine within 30 days prior to study entry.
• Has a clinical condition that in the site investigator's opinion would interfere with study participation.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• Otsuka Pharmaceutical Development & Commercialization, Inc.: collaborator

Study Sites (31)

Gaborone CRS

Gaborone, South-East District, Botswana

Location

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Rio de Janeiro, 21040-360, Brazil

Location

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS

Port-au-Prince, HT-6110, Haiti

Location

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, HT-6110, Haiti

Location

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, Maharashtra, 411001, India

Location

YRG CARE CRS [Site ID: 32075]

Chennai, Tamil Nadu, 600010, India

Location

Moi University Clinical Research Center (MUCRC) CRS

Eldoret, Rift Valley, 30100, Kenya

Location

Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS

Kericho, Rift Valley, 20200, Kenya

Location

Socios En Salud Sucursal Perú CRS

Lima, 15001, Peru

Location

Barranco CRS

Lima, 15063, Peru

Location

San Miguel CRS

Lima, 32-15088, Peru

Location

De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC)

Cavite, 4114, Philippines

Location

Soweto ACTG CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Wits Helen Joseph Hospital CRS (Wits HJH CRS)

Johannesburg, Gauteng, 2092, South Africa

Location

Durban International Clinical Research Site CRS

Durban, KwaZulu-Natal, 4052, South Africa

Location

PHRU Matlosana CRS

Klerksdorp, North West, 2574, South Africa

Location

Rustenburg CRS

Rustenburg, North West, 0300, South Africa

Location

Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS

Cape Town, Western Cape, 7505, South Africa

Location

Task Applied Science (TASK) CRS

Cape Town, Western Cape, 7530, South Africa

Location

University of Cape Town Lung Institute (UCTLI) CRS

Cape Town, Western Cape, 7700, South Africa

Location

South African Tuberculosis Vaccine Initiative (SATVI) CRS

Cape Town, Western Cape, 7705, South Africa

Location

CAPRISA eThekwini CRS

Durban, 4001, South Africa

Location

Kilimanjaro Christian Medical Centre (KCMC)

Moshi, Tanzania

Location

Thai Red Cross AIDS Research Centre (TRC-ARC) CRS

Pathum Wan, Bangkok, 10330, Thailand

Location

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, 10700, Thailand

Location

Chiangrai Prachanukroh Hospital NICHD CRS

Chiang Mai, 50100, Thailand

Location

Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site

Kampala, Uganda

Location

MU-JHU Research Collaboration (MUJHU CARE LTD) CRS

Kampala, Uganda

Location

National Lung Hospital CRS (Site ID: 32483)

Vĩnh Phúc, Hanoi, 100000, Vietnam

Location

Vietnam-University of Sydney CRS Site# 32495

Hochiminh City, 70000, Vietnam

Location

Milton Park CRS

Milton Park, Harare, Zimbabwe

Location

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant; Tuberculosis

Interventions

OPC-67683; Isoniazid; Pyridoxine; Vitamin B 6

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Picolines

Study Officials

• Gavin Churchyard, MBBCh MMed FRCP FCP(SA) PhD

  Aurum Institute

  STUDY CHAIR

• Amita Gupta, MD, MHS

  Johns Hopkins Medical Institutions, Center for Clinical Global Health Education

  STUDY CHAIR

• Anneke Hesseling, MD, PhD

  University of Stellenbosch

  STUDY CHAIR

• Susan Swindells, MBBS

  University of Nebraska

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 14, 2018
• First Posted: June 26, 2018
• Study Start: June 3, 2019
• Primary Completion (Estimated): January 11, 2027
• Study Completion (Estimated): January 11, 2027
• Last Updated: June 15, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
• Access Criteria: * With whom? * Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group. * For what types of analyses? * To achieve aims in the proposal approved by the AIDS Clinical Trials Group. * By what mechanism will data be made available? * Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

Locations

PE (3); ZA (10); HA (2); PH (1); BR (1); UG (2); TH (3); IN (2); BO (1); VN (2); ZI (1); TA (1); KE (2)